Progesterone and estrogen have opposing effects on vaginal physiology. Estrogen promotes vaginal epithelial maturation and decreases pH, while progesterone is an estrogen antagonist. Previously, we showed that systemic progesterone enhanced simian immunodeficiency virus (SIV) vaginal transmission in ovary-intact females. During this grant period we showed that systemic estrogen completely blocked SIV vaginal transmission in ovariectomized (ovx) macaques. Wealso found that SIV vaginal transmission was enhanced in untreated ovx macaques, providing a new model for HIV transmission in post-menopausal women. New results show that the effects of estrogen were confined to the vaginal microenvironment. To capitalize on these findings, we propose to test topical estrogen for prevention of SIV vaginal transmission. The application was extensively revised in response to the critique.'-The studies .'on:humans have beeh_deleted.';In the revision, topical estrogen will be tested in both ovx and in cycling macaques. These experiments will model the post-menopauasal and pre-menopausal states. The new toxicity studies on topical estrogen will use sensitive assays for leutenizing hormone (an indictor of systemic estrogen leakage) and for endometrial hyperplasia. The aims are; Modified Specific Aim 1. To test the safety and efficacy of topical estrogen on SIV-vaginal transmission in ovx macaques. New Aim 2. To test the safety and efficacy of low dose, vaginal estrogen in protecting cycling macaques against SIV vaginal transmission. Using the macaque model, the aims focus on a practical and safe application of our findings to sexually active women,. Sexually active post-menopausal women are a growing risk group. Our studies could provide a method to reduce the risk to this population. The need for protecting pre-menopausal women is self-evident. This multi- disciplinary approach seeks to show prophylactixis in the SIV model that can be directly applied to HTVvaginal transmission. =ERFORMANCE SITE(S) (organization, city, state) 1. Aaron Diamond AIDS Research Center, 455 First Avenue, 7th Floor, New York, NY 10016 2. Tulane Regional Primate Research Center, 18703 Three Rivers Road, Covington, LA 70433 3. St. Michael's Medical Center, 306 Dr. Martin Luther King Jr. Boulevard, Newark, NJ 07103 4. Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, OR 97006 5. Organon, Inc., 375 Mt. Pleasant Avenue, West Orange, NJ 07052 KEY PERSONNEL See instructions on Page Name Preston A. Marx, Ph.D. Stephen M. Smith, M.D. Gary Baskin, D.V.M. David L. Hess, Ph.D. Nancy J. Alexander, Ph.D. 11. Use continuationpages as neededto provide the required information in the format shown below. Organization Role on Project Aaron Diamond AIDS Research Center Principal Investigator St. Michael's Medical Center Co-Investigator Tulane Regional Primate Research Center Co-Investigator pregonJRegional.Primat^Research Center Co-Investigator Organon, Inc. Consultant PHS 398 (Rev. 4/98) Page3 BB KK Principal Investicj^yrogram Director (Last, first, middle): RESEARCH GRANT TABLE OFCONTENTS Page Numbers Face Page 1-2 Description,